NEW YORK A suite of new studies has examined how one cell develops into all the tissues of the human body by tracing and investigating the mutations they acquire over time.
As cells divide, they acquire mutations that are then passed on to their daughter cells. The resulting patterns of mutations can be used to trace back a cell's family tree, possibly all the way to the first cell. In four new studies appearing Wednesday in Nature, teams of researchers from across the world used this approach to study the earliest stages of human development as well as the later accumulation of somatic mutations, including ones linked to cancer.
"Exploring the human body via the mutations cells acquire as we age is as close as we can get to studying human biology in vivo," Luiza Moore, a researcher at the Wellcome Sanger Institute and first author of one of the studies, said in a statement. "Our life history can be found in the history of our cells, but these studies show that this history is more complex than we might have assumed."
Tracing these mutations back in time revealed differences in mutation rates very early in embryonic development. Researchers led by the Sanger Institute's Michael Stratton uncovered a pattern of mutations that indicated a high initial mutation rate that then fell in a study that combined laser capture microdissections with whole-genome sequencing of samples from three individuals. A team led by the Korea Advanced Institute of Science and Technology's Young Seok Ju similarly found a high mutational rate during the early stages of development that then declined, using a capture-recapture approach.
The Stratton-led team estimated that the first two cell divisions had mutation rates of 2.4 per cell per generation, which then fell to 0.7 per cell per generation. This dip, they said, is likely due to the activation of the zygotic genome that increases the ability to repair DNA.
These early cells also contributed unequally to the development of subsequent lineages, though the degree of asymmetry varied from person to person. Ju and his colleagues reported, for instance, that for one individual in their analysis, 112 early lineages split at a ratio of 6.5:1, rather than the expected 1:1.
Stratton and his colleagues, meanwhile, reported that one individual in their study had a 69:31 contribution of the initial daughter cells to subsequent lineages, while another had a 93:7 ratio based on bulk brain samples, but an 81:19 ratio based on colon samples.
This, they said, indicates that the lineage commitment of cells is not fixed. Ju and his colleagues likewise said their finding suggested a stochasticity of clonal segregation in humans, unlike the deterministic embryogenesis observed in C. elegans.
These analyses also shed light on the development of somatic mutations later in life. KAIST's Ju and his colleagues, for instance, found most mutations are specific to certain clones, while in a separate study, the Sanger's Moore and her colleagues, who examined the mutational landscape of 29 cell types from three individuals through sequencing, found mutationrates varied by cell type and were very low in spermatogonia.
Ju and his colleagues also reported that normal tissues harbored known mutational signatures, including UV-mediated DNA damage and endogenous clock-like mutagenesis. Similarly, Moore and her colleagues noted known mutational signatures within normal tissues. They found, for instance, the aging-related SBS1 and SBS5 mutational signatures to be the most common signatures across all cell types, while other signatures were more prominent in certain cell types but not others. The SBS88 signature, which is due to a strain of E. coli, for example, was present among colorectal and appendiceal crypts.
Chen Wu, an investigator at the Chinese Academy of Medical Sciences, and her colleagues also found the aging-related SBS1 and SBS5 mutational signatures to be common among normal tissues, based on their sequencing analysis of microbiopsies from five individuals. Other tissues, like the liver and lung, also harbored other mutational signature like SBS4, which is associated with tobacco smoking.
Some of the mutations present in normal somatic tissues are typically associated with cancer, Wu and her colleagues added. They found mutations in 32 cancer driver genes were widespread among their normal tissue samples, though varied by organ. For instance, driver mutations were present in 6.5 percent of pancreas parenchyma samples and in 73.8 percent of esophageal samples.
Additionally, many normal tissue samples harbored as many as three cancer driver mutations. This, Harvard Medical School's Kamila Naxerova noted in a related commentary in Nature, begins to blur the line between what is normal and what is cancer. "Indeed, if cells with three driver mutations can easily be found in a small tissue sample, cells with four or five drivers probably exist in that tissue as well without necessarily giving rise to cancer," she wrote. "These new insights invite us to reconsider how we genetically define cancer."
Overall, she added that "the four studies provide an impressive demonstration of the power of modern genetics to decode the cellular dynamics that unfold in our bodies over time."
See the article here:
Genetic Analyses Trace How Mutations Accumulate in Cells of the Human Body Over Time - GenomeWeb
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